1. Field of the Invention
The invention generally relates to derivatives of biologically active molecules which show a higher oral bioavailability and therefore higher biological activity than the original biologically active drug.
2. Description of the Relevant Art
Many endogenic substances, natural products and synthetic substances with therapeutically useful properties exhibit a high “first path” effect when administered orally. This means that these molecules are either quickly metabolized or excreted and as a consequence relative high doses need to be applied to ensure the desired biological effect.
Exemplary compounds that exhibit a high first path effect are sexual steroids such as estrogens and androgens. For example, both natural hormones estradiol and testosterone have a low oral bioavailability that significantly limits their application.
There have been intensive efforts over the years to address this shortcoming.
Simple esters like estradiol 17 benzoate or esters of fatty acids as found in testosterone enanthate lead to somewhat improved oral bioavailability.
Sulfonic acid derivatives have proven to be especially promising. In U.S. Pat. No. 5,705,495 and EP 127 35 90 and EP 128 42 73 estradiol sulfonic acid derivatives were described that show higher estrogenic activity after oral administration than estradiol.
One derivative J955 (estradiol sulfamate) was actually selected for development. J995 exhibited a higher estrogenic activity after oral administration than estradiol and ethinyl estradiol in the Allan Doisy test in ovarectomized female rats (Walter Eiger et. Al J. Steroid Biochem. Molec Biol. Vol 55 395-403 1995). Development of J 995 had to be stopped when it was determined that J995 also acted as an inhibitor of sulfatase in women.
In U.S. Pat. No. 7,507,725 and EP 1 294 402 this concept was broadened and generalized to compounds consisting of three distinct moieties Active-ingredient-(Spacer)-SO2NR1R2. These compounds were hypothesized to bind to erythrocytes. The active ingredient could be steroid molecules but also other drugs like diuretics, dopamine agonists and others. The spacer described could consist of either a carbon chain or an aromatic ring or a combination of both.
This concept was later extended to specific substance classes (U.S. Pat. No. 6,841,548; U.S. Pat. No. 6,956,031; U.S. Pat. No. 6,958,327; US 2005/2277625: U.S. Pat. No. 7,534,780; WO 03/104253).
Although the described compounds showed some higher activity than the parent drugs in certain biological tests, the very nature of the described spacer and the sulfonamide moiety lead to compounds with a very low aqueous solubility that limits their use as potential drugs significantly.